administration of melpida to determine the safety and efficacy for patients with spastic paraplegia type 50

Conditions: Spastic Paraplegia Type 50

Summary: this will be a first-in-human phase i, open-label, single dose clinical study of melpida administered intrathecally (it) through a lumbar puncture (lp) to a single subject with confirmed pathogenic mutations in the adaptor related protein complex 4 subunit mu 1 (ap4m1) gene. the primary outcome will be the determination of the safety and tolerability of melpida in patients with spg50, based on development of toxicity. the secondary outcome will be a preliminary exploration of efficacy of the treatment. melpida, is a recombinant serotype 9 adeno-associated virus (aav) encoding a codon-optimized human ap4m1 transgene and will be administer to the patient via a single intrathecal infusion of 10 ml at 1e14 vg/ml for a total dose of 1e15 vg. the total study duration is 5 years post dosing and the participant will be tested at screening/baseline (-28 to -7 days), return for dosing, and then follow-up visits post-dosing on days 7 (+/-2), 30 (+/-2), 60 (+/-2), 90 (+/-14), 180 (+/-14), 270 (+/-14), 360 (+/-14), 540 (+/-14), and 720 (+/-14) days, then annually for the last 3 years.


Eligibility criteria:
inclusion criteria: * age \< 5 years old * confirmed diagnosis of spg50 disease by: * genomic dna mutation analysis demonstrating homozygous or compound heterozygous, pathogenic and/or potentially pathogenic variants in the ap4m1 gene * clinical history or examination features consistent with spg50 and that include neurologic dysfunction * parent/legal guardian willing to provide written informed consent for their child prior to participation in the study * subject able to comply with all protocol requirements and procedures exclusion criteria: * inability to participate in study procedures (as determined by the site investigator) * presence of a concomitant medical condition that precludes lumbar puncture (lp) or use of anesthetics * history of bleeding disorder or any other medical condition or circumstance in which lumbar puncture is contraindicated according to local institutional policy * inability to be safely sedated in the opinion of the clinical anesthesiologist * active infection, at the time of dosing, based on clinical observations * concomitant illness or requirement for chronic drug treatment that in the opinion of the pi creates unnecessary risks for gene transfer * inability of the patient to undergo mri according to local institutional policy * inability of the patient to undergo any other procedure required in this study * the presence of significant non-spg50 related central nervous system (cns) impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study * have received an investigational drug within 30 days prior to screening or plan to receive an investigational drug (other than gene therapy) during the study. * enrollment and participation in another interventional clinical trial * contraindication to melpida or any of its ingredients * contraindication to any of the immune suppression medications used in this study * clinically significant abnormal laboratory values (ggt, alt, and ast, or total bilirubin \> 3 × upper limit of normal (uln), creatinine ≥ 1.5 mg/dl, hemoglobin \[hgb\] \ 20 g/dl; white blood cell (wbc) \> 20,000 per cmm) prior to gene replacement therapy. patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded